Effects of 2,3-dimercapto-1-propanesulfonic acid (DMPS) on methylmercury-induced locomotor deficits and cerebellar toxicity in mice
Effects of 2,3-dimercapto-1-propanesulfonic acid (DMPS) on methylmercury-induced locomotor deficits and cerebellar toxicity in mice
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DOI：
10.1016/j.tox.2007.07.009
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发表时间：
2007-10-08
期刊：
影响因子：
4.5
通讯作者：
Farina, Marcelo
中科院分区：
文献类型：
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作者：
Carvalho, Marcia C.;Franco, Jeferson L.;Farina, Marcelo
螯合疗法已被报道为对抗汞毒性的有效方法。此外，2，3-二巯基丙磺酸（DMPS），一种组织可渗透的金属螯合剂，发现增加尿汞排泄和降低甲基汞（MeHg）暴露后大鼠脑中汞含量。我们评估了DMPS减少成年小鼠甲基汞诱导的运动障碍和小脑毒性的能力。动物在17天内暴露于甲基汞（40毫克/升的饮用水，随意）。在暴露的最后3天（第15-17天），动物接受DMPS注射（150 mg/kg，i. p.;一天一次），以逆转甲基汞诱导的神经毒性。最后一次注射后24小时（第18天），进行与运动功能相关的行为测试（旷场和旋转棒任务）和氧化应激相关参数的生化分析（小脑谷胱甘肽、蛋白硫醇和丙二醛水平、谷胱甘肽过氧化物酶和谷胱甘肽还原酶活性）。还进行了定量小脑中细胞损伤和汞沉积的组织学分析。甲基汞暴露引起了显着的运动缺陷，观察到减少运动活动在开放领域和减少失败的潜伏期在旋转装置。DMPS治疗显示对这些行为参数的改善作用。小脑谷胱甘肽和蛋白巯基水平没有改变甲基汞或DMPS治疗。相反，小脑硫代巴比妥酸反应物质（TBARS），脂质过氧化反应的标志物，在甲基汞暴露的小鼠和DMPS管理最大限度地减少这种现象的水平增加。小脑谷胱甘肽过氧化物酶活性降低甲基汞暴露的动物，但DMPS治疗没有防止这种事件。组织学分析表明，甲基汞处理的小鼠小脑浦肯野细胞数量减少，这种现象完全逆转DMPS治疗。在甲基汞暴露的动物中观察到小脑皮质中的显着汞沉积（颗粒层>浦肯野细胞>分子层），并且DMPS治疗对这些现象显示出显着的改善作用。这些结果表明，DMPS显示出有益的作用，逆转甲基汞诱导的运动缺陷和小脑损伤的小鼠。组织学分析表明，这些现象与其清除小脑皮质汞的能力有关。(c)2007爱思唯尔爱尔兰有限公司保留所有权利。
Chelating therapy has been reported as a useful approach for counteracting mercurial toxicity. Moreover, 2,3-dimercapto-lpropanesulfonic acid (DMPS), a tissue-permeable metal chelator, was found to increase urinary mercury excretion and decrease mercury content in rat brain after methylmercury (MeHg) exposure. We evaluated the capability of DMPS to reduce MeHg-induced motor impairment and cerebellar toxicity in adult mice. Animals were exposed to MeHg (40 mg/L in drinking water, ad libitum) during 17 days. In the last 3 days of exposure (days 15-17), animals received DMPS injections (150 mg/kg, i.p.; once a day) in order to reverse MeHg-induced neurotoxicity. Twenty-four hours after the last injection (day 18), behavioral tests related to the motor function (open field and rotarod tasks) and biochemical analyses on oxidative stress-related parameters (cerebellar glutathione, protein thiol and malondyaldehyde levels, glutathione peroxidase and glutathione reductase activities) were carried out. Histological analyses for quantifying cellular damage and mercury deposition in the cerebellum were also performed. MeHg exposure induced a significant motor deficit, observed as decreased locomotor activity in the open field and decreased failing latency in the rotarod apparatus. DMPS treatment displayed an ameliorative effect toward such behavioral parameters. Cerebellar glutathione and protein thiol levels were not changed by MeHg or DMPS treatment. Conversely, the levels of cerebellar thiobarbituric acid reactive substances (TBARS), a marker for lipid peroxidation, were increased in MeHg-exposed mice and DMPS administration minimized such phenomenon. Cerebellar glutathione peroxidase activity was decreased in the MeHg-exposed animals, but DMPS treatment did not prevent such event. Histological analyses showed a reduced number of cerebellar Purkinje cells in MeHg-treated mice and this phenomenon completely reversed by DMPS treatment. A marked mercury deposition in the cerebellar cortex was observed in MeHg-exposed animals (granular layer > Purkinje cells > molecular layer) and DMPS treatment displayed a significant ameliorative effect toward these phenomena. These findings indicate that DMPS displays beneficial effects on reversing MeHg-induced motor deficits and cerebellar damage in mice. Histological analyses indicate that these phenomena are related to its capability of removing mercury from cerebellar cortex. (c) 2007 Elsevier Ireland Ltd. All rights reserved.